Cytokeratin 15 Marks Basal Epithelia in Developing Ureters and Is Upregulated in a Subset of Urothelial Cell Carcinomas

Abstract

The mammalian ureter contains a water-tight epithelium surrounded by smooth muscle. Key molecules have been defined which regulate ureteric bud initiation and drive the differentiation of ureteric mesenchyme into peristaltic smooth muscle. Less is known about mechanisms underlying the developmental patterning of the multilayered epithelium characterising the mature ureter. In skin, which also contains a multilayered epithelium, cytokeratin 15 (CK15), an acidic intermediate filament protein, marks cells whose progeny contribute to epidermal regeneration following wounding. Moreover, CK15+ precursor cells in skin can give rise to basal cell carcinomas. In the current study, using transcriptome microarrays of embryonic wild type mouse ureters, Krt15, coding for CK15, was detected. Quantitative polymerase chain reaction analyses confirmed the initial finding and demonstrated that Krt15 levels increased during the fetal period when the ureteric epithelium becomes multilayered. CK15 protein was undetectable in the ureteric bud, the rudiment from which the ureter grows. Nevertheless, later in fetal development, CK15 was immunodetected in a subset of basal urothelial cells in the ureteric stalk. Superficial epithelial cells, including those positive for the differentiation marker uroplakin III, were CK15-. Transformation-related protein 63 (P63) has been implicated in epithelial differentiation in murine fetal urinary bladders. In wild type fetal ureters, CK15+ cells were positive for P63, and p63 homozygous null mutant ureters lacked CK15+ cells. In these mutant ureters, sections of the urothelium were monolayered versus the uniform multilayering found in wild type littermates. Human urothelial cell carcinomas account for considerable morbidity and mortality. CK15 was upregulated in a subset of invasive ureteric and urinary bladder cancers. Thus, in ureter development, the absence of CK15 is associated with a structurally simplified urothelium whereas, postnatally, increased CK15 levels feature in malignant urothelial overgrowth. CK15 may be a novel marker for urinary tract epithelial precursor cells.

Long-lived keratin 15+ esophageal progenitor cells contribute to homeostasis and regeneration

“…Basal cell carcinomas also arise from the hair follicle and more specifically from the Krt15 + cells (23). Furthermore, Krt15 also marks the ureter epithelium, and its expression is increased in a subset of urothelium cell carcinomas (24). Given its critical role in epidermal renewal, repair, and cancer development, investigation of Krt15 + cells may provide critical insights into a putative esophageal stem cell population.…”

The monoclonal antibody EPR1614Y against the stem cell biomarker keratin K15 lacks specificity and reacts with other keratins

“…The EPR1614Y antibody has been widely used to study K15 expression as a biomarker of epidermal stem cells in scar formation 63 , differentiation of human hair follicle cells into neurons 64 , psoriatic skin lesions 50 , ameloblastoma 65 , mammary epithelium 66 , developing ureters 67 and human cornea 37 . In view of our data that EPR1614Y would react with cell cytoskeleton even when K15 is absent, some of the published work in which this antibody has been used may require reinterpretation.…”

Molecular analyses of prostate tumors for diagnosis of malignancy on fine-needle aspiration biopsies

“…However, the mechanisms underlying the role of HOXA7, inducing PCa to invade and metastasize, remain unclear. Woolf suggested that the KRT15 gene, encoding for CK15, might be a novel marker for urinary tract epithelial precursor cells [ 27 ]. ITGBL1 (Integrin, beta-like 1) is a β-integrin-related extracellular matrix protein and contains ten EGF-like repeats that dominate as a gene in the osteoblast-like gene-expression signature [ 28 ], which was highly expressed in ovarian cancer tissues and could promote cancer cell migration and invasion [ 29 ], and facilitated the acquisition of tumor cell advantages in recruiting, residing, and organ selectivity to the bone during breast cancer metastasis [ 28 ].…”